Tuberous Twosome

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Science  18 Jun 2010:
Vol. 328, Issue 5985, pp. 1455
DOI: 10.1126/science.328.5985.1455-b

Genetic mutations can lead to the uncontrolled growth of cells; many of these mutations either activate oncogenes or inactivate tumor suppressor genes. However, it has become apparent that inhibiting mutated proteins via small-molecule drugs is nontrivial, and rescuing inactivated tumor suppressors, such as retinoblastoma (Rb), is equally challenging. To tackle these problems, cancer biologists have turned to synthetic lethality, which refers to the interaction between two genes when disrupting the activity of both together causes a cell to die, whereas inactivation of either gene alone has no significant effect.

Li et al. have used a genetic screen in Drosophila to identify genes that interact in a synthetic lethal manner with Rb. They identified the homolog of tuberous sclerosis complex 2 (TSC2), whose inactivation, along with that of Rb, induced cell death both in Drosophila and in human cancer cells growing in culture and in mouse xenografts. Lethality was due in part to an increase in oxidative stress. The capacity to identify genes that are deadly only within the context of a cancer cell could yield targeted therapeutics that would leave normal cells largely unaffected and thereby reduce the toxic side effects characteristic of many chemotherapeutic agents in use in the clinic.

Cancer Cell 17, 469 (2010).

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